The central goal of this K24 renewal application is to further my development as a clinical investigator, while enhancing my opportunities and skills in the mentorship of fellows and promising young faculty interested in careers in clinical research. Patient-oriented clinical research has been the cornerstone of my medical career. My main research focus has been the investigation of asymptomatic primary hyperparathyroidism (PHPT). In recent years, my research has concentrated on the non-classical manifestations of PHPT, and the studies in this thematically related K24 program are focused in this area. My research goal is to continue to develop this program. All three themes of this renewal application were highlighted by the 3rd International Workshop on Asymptomatic PHPT (J Clin Endocrinol Metab 94:335-9, 2009) as key areas for future investigation. The themes and Specific Aims (SA's) of this research are: Theme 1. Vitamin D deficiency in PHPT: SA1a. To compare biochemical and skeletal features of PHPT patients with and without co-existing vitamin D deficiency. SA1b. To investigate the early effects of vitamin D repletion in PHPT on static and dynamic histomorphometric parameters of bone remodeling (by quadruple labeled bone biopsy). Theme 2. Cardiovascular manifestations of PHPT: SA2a. To determine whether or not abnormalities in cardiovascular structure or function in patients with asymptomatic PHPT are reversible after parathyroidectomy. SA2b. To investigate the hypothesis that some of the cardiovascular manifestations of PHPT are due to low vitamin D levels, rather than elevated calcium and PTH levels, by comparing left ventricular mass index and carotid intima medial thickness in PHPT patients with and without vitamin D deficiency. Theme 3. Neurocognitive manifestations of PHPT SA3a. To further investigate neurocognitive abnormalities in PHPT by assessing site-specific changes in brain metabolism after parathyroidectomy using the innovative technique of functional MRI. SA3b. To determine whether the neuropsychological abnormalities seen in hypercalcemic PHPT are present in normocalcemic PHPT. Although outside of the closely-knit theme of the K24, there are other ongoing and future opportunities for mentored research (i.e. theme: obesity/bariatric surgery and the skeleton: 3 mentored studies ongoing). Importantly, the proposal will provide many opportunities to mentor junior investigators. I have had success as a mentor, with 16 current or past trainees, 10 of whom have been mentored under the current K24 award. Seven of the 10 remain in academic medicine. Of those I have mentored, 3 currently hold and 1 recently completed NIH K23 Awards, 3 completed Masters in POR (2 under my mentorship) and 2 received Endocrine Fellows Foundations grants. One mentee, who has worked with me since her fellowship began, was awarded a NIH stimulus grant. As Co-Director of our NIH Postdoctoral Fellowship Program and Director of the 4th yr Endocrinology Elective in the medical school, I have ongoing access to medical students, residents, Endocrine Fellows and junior faculty who are interested in my research. There has also been interest in my research from trainees in other disciplines (current cardiology fellow Iwata), enhancing my potential to add interdisciplinary perspectives to POR in metabolic bone diseases that should enhance our field. My mentorship goals for this K24 are both to have the opportunity to mentor, and to further develop my mentorship skills. New directions for mentorship will include: 1. I will develop a new program to educate mentors in the Department of Medicine; creating a curriculum for developing mentoring skills and convening mentors to share and refine best practices. 2. I will expand my mentoring in new directions: a) outside of my research area as a Mentor in the Department of Medicine Faculty Development Program; and b) within my research area but outside of Columbia in online mentorship programs (ASBMR Mentor Matching program and The Endocrine Society's Mentor Exchange). I will develop new mentorship skills, learning to transmit critical information electronically rather than in person and by example. 3. Coursework at Columbia on: mentoring, FDA regulated research and research with minors will sharpen and expand my tools for mentoring. The environment at Columbia is outstanding, with a large and supportive Endocrine Division, an excellent NIH funded Clinical Research Center and CTSA, which offers my mentees the opportunity for didactic enrichment in POR through their Master of Science in POR program (Columbia University Mailman School of Public Health and CTSA). Both the Department of Medicine and the GCRC have made substantial commitments toward my development as a clinical investigator. The initial K24 funding period allowed me to reduce my clinical, administrative and teaching loads in order to devote more time to clinical research and to training and mentoring junior faculty and fellows. This award remains an ideal mechanism to allow me to achieve my dual goals: continued productivity in the clinical investigation of parathyroid disease, with protected time for mentoring fellows and junior colleagues interested in patient oriented clinical research as a career path. PUBLIC HEALTH RELEVANCE: The research in this K24 renewal application is designed to address several areas identified as key directions for future research by the 2008 International Workshop on Asymptomatic Primary Hyperparathyroidism. These include vitamin D deficiency in primary hyperparathyroidism, as well as the cardiovascular and neurocognitive manifestations of the disease. The new knowledge that will be generated by the work described in this proposal will have its own intrinsic value and clinical applicability. It will also serve as a vehicle for m to continue mentoring young clinicians interested in a career in patient-oriented research (POR). In addition to providing mentoring, this award will allow me to further develop my mentoring skills through new initiatives in and outside of my area of research, both locally (at Columbia) and nationally/internationally. I am fully committed to overseeing the best possible outcome in both the Mentorship and Research arenas. ! !